This invention relates to di and tri-O-acetyl-4"-O-iso-valeryl-23-O-demycinosyltylosins, hydrazone derivatives thereof and a process for their preparation. This invention also relates to processes for the preparation of di-, tri- and tetra-O-acyl-23-O-demycinosyltylosin derivatives. The present invention further relates to selective acylation processes for preparing 2',4",4'"-tri-O-acyltylosin and 3,2',4",4'"-tetra-O-acyltylosin and selective deacylation process for preparation of 3,4"-di-O-acyltylosin.
Tylosin and numerous derivatives thereof are known in the antibiotic art. However, tylosin and 23-O-demycinosyltylosin are readily transformed in acidic and basic solution into aldol condensation and Michael addition products. See for example H. Matsubara et al., Chem. Pharm. Bull. (Japan), Vol. 30, pp 97-110 (1982); S. Omura et al., The Journal of Antibiotics, Vol. XXXVII, pp 1007-1015 (1984); N.N. Girotra et al., Tetrahedron, Vol. 32, pp 991-993 (1976); T. Suzuki et al., Chemistry Letters (Japan), pp 793-798 (1973); and S. Omura et al. The Journal of Antibiotics, Vol. XXVII, pp 370-372 (1974). Accordingly, microbiological acylation and the use of labile acyl groups which can be easily and selectively removed have been utilized by prior art workers to avoid formation of side product.
U.S. Pat. No. 4,436,733 discloses a large genus of tylosin analogs. Specifically, it discloses 4"-and 3-mono-and 3,4"-di-O-acyl derivatives of 23-O-demycinosyltylosin and 23-demycinosyloxytylosin. The compounds of this invention are not specifically disclosed therein. The acylation procedure described in U.S. Pat. No. 4,436,733 requires use of highly labile acyl groups such as phenoxyacetyl and mono- and tri-haloacetyl.
A. Hassner et al. in Tetrahedron, Vol. 34, pp 2069-2076 (1978) disclose use of catalytic amounts (0.02 to 0.1 equivalents) amount of 4-aminopyridines such as 4-(dimethylamino)pyridine (DMAP) as acylation catalysts for unreactive alcohols at room temperature. U.S. Pat. No. 4,454,314 at col. 25, lines 53-65 discloses use of catalytic amounts of DMAP for selective acylation of the C-3 secondary hydroxyl group of tylosin derivative.
UK Patent Application 2,077,731 discloses 23-O-demycinosyltylosin and its 20-dihydro derivatives which are allegedly useful against Gram-positive bacteria and Mycoplasma species. In the compounds disclosed, when the 3-position of the molecule is occupied by an O-acetyl group, the 4" position cannot be occupied by an O-iso-valeryl group. Also, disclosed therein is a microbiological process for producing 23-O-demycinosyltylosin by culturing strains of Streptomyces fradiae under submerged aerobic fermentation conditions.
U.S. Pat. No. 4,205,163 discloses the preparation of 4"-O-acyl- and 3,4"-di-O-acyltylosin from tylosin or 3-acyltylosin. However, the preparation requires introduction of highly labile 4'"-O-acyl groups such as ethoxycarbonyl, phenoxycarbonyl or haloacetyl which can easily be selectively removed.
Belgian Patent No. 849,847 discloses preparation of 3-O-acyl-4"-O-iso-valeryltylosin by the microbiological acylation of the 3 and 4" hydroxyl groups of tylosin by a mutant organism.
The preparation of 3-O-acetyl-4"-O-iso-valeryl-23-O-demycinosyltylosin directly by mutasynthesis has also been described in Japanese Patent No. 85-16960.
The preparation of DMT by mutasynthesis is described in European Patent No. 96,900.
U.S. Pat. No. 4,396,613 discloses 23-ester derivatives of 23-O-demycinosyltylosin useful as antibiotics and/or as intermediates to antibiotics. The 23-ester derivatives are chemically prepared from 23-O-demycinosyltylosin or from 2'-O-ester derivatives of 23-O-demycinosyltylosin.
U.S. Pat. No. 4,436,729 discloses 23-O-demycinosyltylosin and derivatives thereof which are useful as antibacterials. In addition, there is disclosed a chemical synthesis of 23-O-demycinosyltylosin from suitably protected tylosin derivatives. Selective acylation of 23-O-demycinosyltylosin is also described therein.
U.S. Pat. No. 4,321,361 discloses 23-O-demycinosyltylosin and its 20-dihydro derivatives which are allegedly useful as antibacterial agents active against Gram-positive microorganisms and Mycoplasma species. A generic group of esters is disclosed therein and specifically mono esters of the 2'-hyroxyl group are disclosed. The 23-O-demycinosyltylosin is prepared by mutasynthesis, specifically by culturing Streptomyces fradiae under submerged aerobic fermentation conditions until a substantial level of antibiotic activity is produced.
Continued extensive use of effective antibacterial agents has given rise to resistant strains of pathogens and to the continuing need for new antibacterial agents, particularly those with high serum and tissue levels.
Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy, and improved pharmaceutical properties e.g., greater oral absorption, higher serum or tissue concentration, longer body half life, and more advantageous rate or route of excretion and rate or pattern of metabolism are some of the goals for improved antibacterials.
There is a need for processes for the preparation of di-, tri- and tetra-O-acyltylosins and di-, tri- and tetra-O-aceyl-23-O-demycinosyltylosins which do not rely on the use of microbiological pathways which do not require the use of 3-O-acetyltylosin as the starting material and which do not require the use of highly labile acyl groups to avoid formation of undesirable side products.